Delayed central tolerance of IGRP specific T cells is mediated by IGRP-expressing peripheral dendritic cells (83.28)

Abstract

Abstract Prevention of autoimmunity requires the elimination of self-reactive T cells during their development in the thymus and maturation in the periphery. Due to central and peripheral tolerance, transgenic NOD mice that overexpress islet specific glucose 6 phosphatase catalytic subunit related protein (IGRP) in antigen presenting cells, under the control of the class II MHC promoter, have no IGRP specific T cells. Peripheral tolerance of IGRP-specific T cells was mediated by both stromal cells and bone marrow derived APCs. However, central tolerance was mediated only by bone marrow-derived APCs. Moreover, central tolerance was age dependent, occurring only after 10 weeks and was not related to thymic involution, change in the absolute number of dendritic cells or the amount of IGRP expression. Age-dependent central tolerance was mediated by an increased proportion of thymus homing, signal regulatory protein alpha-positive CD8alpha negative dendritic cells. This provides in vivo data to indicate the potential feasibility of inducing central tolerance with DC therapy. They also raise the possibility that the efficiency of central tolerance might increase with age.